The present invention generally falls within the therapeutic field and more particularly within the field of therapy for neoplastic pathologies.
The enzyme creatine kinase (EC 2.7.3.2, CK) plays an essential role in the energy metabolism of cells (Saks et al 1975; Seraydarian and Abbott 1976). The said enzyme is ubiquitous and capable of transferring phosphate groups from ATP to creatine and from phosphocreatine to ADP, allowing for the recharging of ATP. In the proximity of mitochondria, the enzyme creatine kinase catalyzes the phosphorylation of creatine, thereby generating ADP and phosphocreatine. In the cell areas that require more energy, creatine kinase transfers the phosphate group from phosphocreatine to ADP to restore ATP, thus supporting the cell's energy requirements.
The enzyme creatine kinase has a molecular weight of approximately 60 KDa and is made of four subunits: two cytosolic, M-CK and B-CK, and two mitochondrial, “ubiquitous” uMt-CK and “sarcomeric” sMt-CK (Joseph et al 1997; Griffiths 1982).
The two cytosolic subunits are the M (from muscle) subunit and the B (from brain) subunit. The genes that express them are distributed on two different chromosomes: chromosome 14q32 for subunit B and chromosome 19q13 for subunit M (Stallings et al 1988). The combination thereof leads to three different isoforms expressed in the districts that re quire more energy (Walliman et al 1992; Wyss et al 1992): the muscle isoenzyme (CK-MM), the heart isoenzyme (CK-MB) and the brain isoenzyme (CK-BB). The three isoenzymes catalyze the same reaction, namely the reversible transfer of the ATP gamma-phosphate group to the guanidine group of creatine, thereby obtaining phosphocreatine and ADP.
A number of studies have demonstrated that the activity of the creatine kinase enzyme is involved in the growth of cancer (Joseph et al 1997; Li et al 2013; Zhang et al 2009), with its several isoenzymes having different roles in the neoplastic tissues (Kristensen et al 1999). For instance, the brain isoenzyme (CK-BB) was shown to be involved in the tumorigenesis process (Kaddurah-Daouk et al 1990).
A few chemical inhibitors of the creatine kinase enzyme are known. Iodoacetamide is an, alkylating agent that provides complete and irreversible inhibition on the enzyme (Rodriguez et al 2003; Ren et al 2009). The 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one is an α-β-unsaturated ketone used in various industrial productions and as an anti-detonating additive in petrol (Fairhill 1969; Yarema and Curry 2005). It is a competitive inhibitor of the creatine kinase enzyme (De Andrade et al 2010; De Andrade et at 2012).
In consideration of the role played by creatine kinase in the development of cancer, the use of cyclocreatine as treatment against cancer has been studied (Martin et al 1994). This molecule has been found suitable for inhibiting tumor cell lines that express a high level of creatine kinase (Lillie et al 1993). The antitumor action of other creatine analogues has also been assessed (Bergnes et al 1996).